title: Ribosomal S6 Kinase 2 (RSK2) maintains genomic stability by activating the Atm/p53-dependent DNA damage pathway.
abstract: Ribosomal S6 Kinase 2 (RSK2) is a member of the p90(RSK) family of serine/threonine kinases, which are widely expressed and respond to many growth factors, peptide hormones, and neurotransmitters. Loss-of function mutations in the RPS6KA3 gene, which encodes the RSK2 protein, have been implicated in Coffin-Lowry Syndrome (CLS), an X-linked mental retardation disorder associated with cognitive deficits and behavioral impairments. However, the cellular and molecular mechanisms underlying this neurological disorder are not known. Recent evidence suggests that defective DNA damage signaling might be associated with neurological disorders, but the role of RSK2 in the DNA damage pathway remains to be elucidated. Here, we show that Adriamycin-induced DNA damage leads to the phosphorylation of RSK2 at Ser227 and Thr577 in the chromatin fraction, promotes RSK2 nuclear translocation, and enhances RSK2 and Atm interactions in the nuclear fraction. Furthermore, using RSK2 knockout mouse fibroblasts and RSK2-deficient cells from CLS patients, we demonstrate that ablation of RSK2 impairs the phosphorylation of Atm at Ser1981 and the phosphorylation of p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress. We also show that RSK2 affects p53-mediated downstream cellular events in response to DNA damage, that RSK2 knockout relieves cell cycle arrest at the G2/M phase, and that an increased number of γH2AX foci, which are associated with defects in DNA repair, are present in RSK2-deficient cells. Taken together, our findings demonstrated that RSK2 plays an important role in the DNA damage pathway that maintains genomic stability by mediating cell cycle progression and DNA repair.
authors.affiliation: Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore, Singapore.
authors.forename: Han Chi
authors.initials: HC
authors.lastname: Lim
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Zhong-Can
authors.initials: ZC
authors.lastname: Chen
authors.forename: Guang-Zhi
authors.initials: GZ
authors.lastname: Wu
authors.forename: Shu-Sen
authors.initials: SS
authors.lastname: Cui
authors.forename: Eng King
authors.initials: EK
authors.lastname: Tan
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D004249:DNA Damage; D042822:Genomic Instability; D006801:Humans; D009153:Mutagens / Q000633:toxicity; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D009153:Mutagens; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3